Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex

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dc.authoridRangarajan, Parthasarathy/0009-0003-5955-397X
dc.authoridWeir, Scott/0000-0002-8020-434X
dc.contributor.authorWeir, Scott J.
dc.contributor.authorDandawate, Prasad
dc.contributor.authorStanding, David
dc.contributor.authorBhattacharyya, Sangita
dc.contributor.authorRamamoorthy, Prabhu
dc.contributor.authorRangarajan, Parthasarathy
dc.contributor.authorWood, Robyn
dc.date.accessioned2025-02-06T17:58:23Z
dc.date.available2025-02-06T17:58:23Z
dc.date.issued2021
dc.departmentAltınbaş Üniversitesien_US
dc.description.abstractCiclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to gamma -secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235mg/kg and 470mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).en_US
dc.description.sponsorshipNIH [CA182872]; Institute for Advancing Medical Innovation (IAMI) at the University of Kansas Medical Center; Lead Development and Optimization Shared Resource (LDOSR) of the NCI [CA168524]; NIH COBRE grant [RR016443]; NIH CCSG grant [CA168524]en_US
dc.description.sponsorshipStudies were supported by an NIH grant CA182872 to S.A. and S.J.W., and the Institute for Advancing Medical Innovation (IAMI) at the University of Kansas Medical Center, established through a grant provided to SJW by the Ewing Marion Kauffman Foundation. Drug discovery and development resources were provided by the Lead Development and Optimization Shared Resource (LDOSR) of the NCI-supported University of Kansas Cancer Center Core Support Grant (CCSG, CA168524). The Flow Cytometry Core Laboratory is supported by the NIH COBRE (RR016443) and CCSG grants (CA168524).en_US
dc.identifier.doi10.1038/s41419-021-03836-z
dc.identifier.issn2041-4889
dc.identifier.issue6en_US
dc.identifier.pmid34059639
dc.identifier.scopus2-s2.0-85107321009
dc.identifier.urihttps://doi.org/10.1038/s41419-021-03836-z
dc.identifier.urihttps://hdl.handle.net/20.500.12939/5213
dc.identifier.volume12en_US
dc.identifier.wosWOS:000659123100003
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoenen_US
dc.publisherSpringernatureen_US
dc.relation.ispartofCell Death & Diseaseen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.snmzKA_WOS_20250206
dc.subjectSuperficial Bladder-Canceren_US
dc.subjectIron Chelatorsen_US
dc.subjectNotch Pathwayen_US
dc.subjectCiclopiroxen_US
dc.subjectExpressionen_US
dc.subjectPharmacokineticsen_US
dc.subjectPathogenesisen_US
dc.subjectProgressionen_US
dc.subjectInhibitorsen_US
dc.subjectUpdateen_US
dc.titleFosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complexen_US
dc.typeArticleen_US

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